Publications by authors named "Michael Doherty"

414 Publications

Association between gut microbiota and symptomatic hand osteoarthritis: data from the Xiangya Osteoarthritis Study.

Arthritis Rheumatol 2021 Mar 24. Epub 2021 Mar 24.

Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.

Objectives: Systemic inflammatory factors have been implicated in symptomatic hand osteoarthritis (SHOA). Gut microbiome dysbiosis promotes systematic inflammation. The aim of the study was to examine the association between gut microbiome with the presence of SHOA in a population-based study.

Methods: Study participants were derived from the Xiangya Osteoarthritis (XO) Study, a community-based observational study. SHOA was defined as the presence of both symptoms and radiographic osteoarthritis in the same hand. The gut microbiome was analyzed using 16S ribosomal RNA sequencing from stool samples. We examined the relation of α diversity, β diversity, relative abundance of gut microbiome and potential bacterial functional pathways based on predictive metagenome profiling to SHOA.

Results: A total of 1,388 participants (women: 57.4%; mean age: 61.3 years; SHOA prevalence: 5.2%) were included. β diversity, but not α diversity, was significantly associated with SHOA (P=0.003). Higher relative abundance of genus Bilophila and Desulfovibrio as well as lower relative abundance of genus Roseburia were associated with SHOA. Most Kyoto Encyclopedia of Genes and Genomes pathways altered in participants with SHOA belonged to amino acid, carbohydrate and lipid metabolic pathways.

Conclusions: This large population-based study provides the first evidence that alteration of gut microbiome composition was observed among participants with SHOA, and low relative abundance of Roseburia but high relative abundance of Bilophila and Desulfovibrio at genus level were associated with prevalent SHOA. Our findings may help understand the role of microbiome in the development of SHOA and contribute to potential translational opportunities.
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http://dx.doi.org/10.1002/art.41729DOI Listing
March 2021

What is the incidence of methotrexate or leflunomide discontinuation related to cytopenia, liver enzyme elevation or kidney function decline?

Rheumatology (Oxford) 2021 Mar 16. Epub 2021 Mar 16.

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objectives: To examine incidence of treatment changes due to abnormal blood-test results and, to explore rates of treatment changes due to liver, kidney and haematological blood-test abnormalities in autoimmune rheumatic diseases (AIRD) treated with low-dose methotrexate or leflunomide.

Methods: Data for people with AIRDs prescribed methotrexate or leflunomide were extracted from the Clinical Practice Research Datalink. Participants were followed-up from first prescription of methotrexate or leflunomide in primary-care. Primary outcome of interest was drug discontinuation, defined as a prescription gap of ≥ 90 days following an abnormal (or severely abnormal) blood-test result. Dose reduction was examined between consecutive prescriptions. Incidence rates per 1,000 person-years were calculated.

Results: 15,670 and 2,689 participants contributing 46,571 and 4,558 person-years follow-up were included in methotrexate and leflunomide cohorts respectively. The incidence of methotrexate and leflunomide discontinuation with abnormal (severely abnormal) blood-test was 42.24(6.16) and 106.53(9.42)/1,000 person-years in year-1, and 22.44(2.84) and 31.69(4.40)/1,000 person-years respectively thereafter. The cumulative incidence of methotrexate and leflunomide discontinuation with abnormal (severely abnormal) blood-tests was 1 in 24(1 in 169), 1 in 9(1 in 106) at 1-year; and 1 in 45(1 in 352), 1 in 32(1 in 227) per-year respectively thereafter. Raised liver enzymes were the commonest abnormality associated with drug discontinuation. Methotrexate and leflunomide dose reduction incidence were comparable in year-1, however, thereafter methotrexate dose was reduced more often than leflunomide (16.60(95% CI; 13.05-21.13) vs. 8.10(95% CI; 4.97-13.20)/1,000 person-years).

Conclusion: Methotrexate and leflunomide were discontinued for blood-test abnormalities after year-1 of treatment, however, discontinuations for severely abnormal results were uncommon.
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http://dx.doi.org/10.1093/rheumatology/keab254DOI Listing
March 2021

β-blocker prescription is associated with lower cumulative risk of knee osteoarthritis and knee pain consultations in primary care: a propensity score matched cohort study.

Rheumatology (Oxford) 2021 Mar 12. Epub 2021 Mar 12.

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objectives: To examine the association between β-blocker prescription and first primary-care consultation for knee osteoarthritis (OA), hip OA, knee pain and hip pain.

Methods: Data source: Clinical Practice Research Datalink. Participants aged ≥40 years in receipt of new oral β-blocker prescriptions were propensity score (PS) matched to an unexposed control. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CI) were calculated, and adjusted for non-osteoporotic fractures, number of primary-care consultations for knee or hip injury, and, the number of primary-care consultations, out-patient referrals and hospitalizations in the 12-months preceding cohort entry. Analysis was stratified according to β-blocker class and for commonly prescribed drugs. p< 0.05 was statistically significant.  .

Results: 111 718 β-blocker exposed participants were 1:1 PS matched to unexposed controls. β-blocker prescription was associated with reduced cumulative risk of knee OA, knee pain, and hip pain consultations with aHR(95%CI) 0.90(0.83-0.98); 0.88(0.83-0.92), and 0.85(0.79-0.90), respectively. Propranolol and atenolol were associated with a lower incidence of knee OA and knee pain consultations with aHRs between 0.78-0.91. β-blockers were associated with reduced incidence of consultation for large-joint lower-limb OA/pain as a composite outcome, defined as earliest of knee OA, knee pain, hip OA or hip pain consultation (aHR(95%CI) 0.87(0.84-0.90)).

Conclusion: Commonly used β-blockers have analgesic properties for musculoskeletal pain. Atenolol might be a therapeutic option for OA and cardiovascular co-morbidities in which β-blockers are indicated, while propranolol may be suitable for people with co-morbid anxiety. A confirmatory randomised controlled trial is needed before clinical practice is changed.
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http://dx.doi.org/10.1093/rheumatology/keab234DOI Listing
March 2021

Metabolic signatures of osteoarthritis in urine using liquid chromatography-high resolution tandem mass spectrometry.

Metabolomics 2021 03 3;17(3):29. Epub 2021 Mar 3.

Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.

Introduction: Osteoarthritis (OA) is a common cause of disability in older people, but its aetiology is not yet fully understood. Biomarkers of OA from metabolomics studies have shown potential use in understanding the progression and pathophysiology of OA.

Objectives: To investigate possible surrogate biomarkers of knee OA in urine using metabolomics to contribute towards a better understanding of OA progression and possible targeted treatment.

Method: Liquid chromatography-high resolution mass spectrometry (LC-HRMS) was applied in a case-control approach to explore the possible metabolic differences between the urinary profiles of symptomatic knee OA patients (n = 74) (subclassified into inflammatory OA, n = 22 and non-inflammatory OA, n = 52) and non-OA controls (n = 68). Univariate, multivariate and pathway analyses were performed with a rigorous validation including cross-validation, permutation test, prediction and receiver operating characteristic curve to identify significantly altered metabolites and pathways in OA.

Results: OA datasets generated 7405 variables and multivariate analysis showed clear separation of inflammatory OA, but not non-inflammatory OA, from non-OA controls. Adequate cross-validation (RY = 0.874, Q = 0.465) was obtained. The prediction model and the ROC curve showed satisfactory results with a sensitivity of 88%, specificity of 71% and accuracy of 77%. 26 metabolites were identified as potential biomarkers of inflammatory OA using HMDB, authentic standards and/or MS/MS database.

Conclusion: Urinary metabolic profiles were altered in inflammatory knee OA subjects compared to those with non-inflammatory OA and non-OA controls. These altered profiles associated with perturbed activity of the TCA cycle, pyruvate and amino acid metabolism linked to inflammation, oxidative stress and collagen destruction. Of note, 2-keto-glutaramic acid level was > eightfold higher in the inflammatory OA patients compared to non-OA control, signalling a possible perturbation in glutamine metabolism related to OA progression.
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http://dx.doi.org/10.1007/s11306-021-01778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925472PMC
March 2021

Temporal relationship between osteoarthritis and comorbidities: a combined case control and cohort study in the UK primary care setting.

Rheumatology (Oxford) 2021 Jan 28. Epub 2021 Jan 28.

Academic Rheumatology, Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, UK.

Objective: To determine the burden of comorbidities in osteoarthritis (OA) and their temporal relationships in the UK.

Methods: The Clinical Practice Research Datalink (CPRD) GOLD was used to identify people with incident OA and age, gender and practice matched non-OA controls from UK primary care. Controls were assigned the same index date as matched cases (date of OA diagnosis). Associations between OA and 49 individual comorbidities and multimorbidity (≥2 comorbidities excluding OA) both before and after OA diagnosis were estimated, adjusting for covariates, using odds ratios (aOR) and hazard ratios (aHR) respectively.

Results: During 1997-2017, we identified 221 807 incident OA cases and 221 807 matched controls. Of 49 comorbidities examined, 38 were associated with OA both prior to, and following, the diagnosis of OA, and 2 (dementia and SLE) were associated with OA only following the diagnosis of OA. People with OA had higher risk of developing heart failure (aHR 1.63; 95% CI 1.56-1.71), dementia (aHR 1.62; 95% CI 1.56-1.68), liver diseases (aHR 1.51; 95% CI 1.37-1.67), irritable bowel syndrome (aHR 1.51; 95% CI 1.45-1.58), gastrointestinal bleeding (aHR 1.49; 95% CI 1.39-1.59), 10 musculoskeletal conditions and 25 other conditions following OA diagnosis. The aOR for multimorbidity prior to the index date was 1.71 (95% CI 1.69-1.74), whereas the aHR for multimorbidity after the index date was 1.29 (95% CI 1.28-1.30).

Conclusions: People with OA are more likely to have other chronic conditions both before and after the OA diagnosis. Further study on shared aetiology and causality of these associations is needed.
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http://dx.doi.org/10.1093/rheumatology/keab067DOI Listing
January 2021

Does glucose influence multidien cycles of interictal and/or ictal activities?

Seizure 2021 Feb 13;85:145-150. Epub 2021 Jan 13.

Swedish Epilepsy Center, 550 17th Ave suite 540, Seattle, WA, 98122, USA. Electronic address:

Purpose: There are multidien patterns of seizure occurrence. Predicting seizure risk may be easier with biomarker correlates to multidien patterns. We hypothesize multiday hyper or hypoglycemia contributes to seizure risk.

Methods: In a type I diabetic (T1D) with focal onset epilepsy with continuous glucose monitoring (CGM) and responsive neurostimulation (RNS) devices, we studied multiday interictal activities (IEA), seizures, and glucose. Hourly CGM data was matched to hourly RNS captures of interictal and ictal activities over 33 months. RNS detection settings were unchanged. Multidien cycles were analyzed, active blocks of IEA and ictal episodes defined, and tissue glucose averages studied.

Results: Average glucose was 161 mg/dl. A 40-day cycle of interictal and ictal activities occurred, though no similar glucose cycle was evident. Glucose elevations relative to patient average were associated with increases in IEA but not seizure. Frequent seizures were not associated with obvious elevations or decreases of glucose from baseline, most seizures occurred at +/- 10 mg/dl of average daily glucose (i.e. 150-170 mg/dl).

Conclusion: Tissue glucose may influence IEA but may not influence multiday seizure activity or very frequent seizures. In an ambulatory T1D patient multiday hypo or hyperglycemic extremes do not appear to provoke seizure activities.
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http://dx.doi.org/10.1016/j.seizure.2020.12.002DOI Listing
February 2021

Exosome Surface Display of IL12 Results in Tumor-Retained Pharmacology with Superior Potency and Limited Systemic Exposure Compared with Recombinant IL12.

Mol Cancer Ther 2021 03 21;20(3):523-534. Epub 2020 Dec 21.

Codiak BioSciences Inc., Cambridge, Massachusetts.

The promise of IL12 as a cancer treatment has yet to be fulfilled with multiple tested approaches being limited by unwanted systemic exposure and unpredictable pharmacology. To address these limitations, we generated exoIL12, a novel, engineered exosome therapeutic that displays functional IL12 on the surface of an exosome. IL12 exosomal surface expression was achieved via fusion to the abundant exosomal surface protein PTGFRN resulting in equivalent potency to recombinant IL12 (rIL12) as demonstrated by IFNγ production. Following intratumoral injection, exoIL12 exhibited prolonged tumor retention and greater antitumor activity than rIL12. Moreover, exoIL12 was significantly more potent than rIL12 in tumor growth inhibition. In the MC38 model, complete responses were observed in 63% of mice treated with exoIL12; in contrast, rIL12 resulted in 0% complete responses at an equivalent IL12 dose. This correlated with dose-dependent increases in tumor antigen-specific CD8 T cells. Rechallenge studies of exoIL12 complete responder mice showed no tumor regrowth, and depletion of CD8 T cells completely abrogated antitumor activity of exoIL12. Following intratumoral administration, exoIL12 exhibited 10-fold higher intratumoral exposure than rIL12 and prolonged IFNγ production up to 48 hours. Retained local pharmacology of exoIL12 was further confirmed using subcutaneous injections in nonhuman primates. This work demonstrates that tumor-restricted pharmacology of exoIL12 results in superior efficacy and immune memory without systemic IL12 exposure and related toxicity. ExoIL12 is a novel cancer therapeutic candidate that overcomes key limitations of rIL12 and thereby creates a therapeutic window for this potent cytokine.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0484DOI Listing
March 2021

Efficacy and safety of multiple intra-articular corticosteroid injections for osteoarthritis-a systematic review and meta-analysis of randomized controlled trials and observational studies.

Rheumatology (Oxford) 2021 Apr;60(4):1629-1639

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objectives: To investigate the efficacy and safety of multiple intra-articular corticosteroid (IACS) injections for the treatment of OA.

Methods: We conducted electronic searches of several databases for randomized controlled trials (RCTs) and observational studies. Standard mean difference was calculated for efficacy, whereas hazard ratio (HR) was used for adverse effects. Results were combined using the random effects model. Heterogeneity was measured using I2 statistics.

Results: Six RCTs were included for efficacy assessment. The use of multiple IACS appeared to be better than comparator (standard mean difference for pain -0.47, 95% CI -0.62, 0.31). However, there was considerable heterogeneity (I2 92.6%) and subgroup analysis by comparator showed no separation of regular IACS from placebo, though timing of pain assessments was questionable. Fourteen RCTs and two observational studies were assessed for the safety of multiple IACS. Minor local adverse events were similar in both groups. One RCT found that regular IACS every 3 months for 2 years caused greater cartilage loss compared with saline injection (-0.21 vs 0.10 mm). One cohort study found that multiple IACS injections associated with worsening of joint space narrowing (HR 3.02, 95% CI 2.25, 4.05) and increased risk of joint replacement (HR 2.54, 95% CI 1.81, 3.57).

Conclusion: Multiple IACS injections are no better than placebo for OA pain according to current evidence. The preliminary finding of a detrimental effect on structural OA progression warrants further investigation. Efficacy and safety of multiple IACS reflecting recommended best practice has yet to be assessed.
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http://dx.doi.org/10.1093/rheumatology/keaa808DOI Listing
April 2021

Pregnancy outcomes in women with epilepsy and MTHFR mutations supplemented with methylated folate and methylcobalamin (methylated B12).

Epilepsy Behav Rep 2021 17;15:100419. Epub 2020 Dec 17.

Swedish Epilepsy Center, Swedish Hospital, Seattle, WA, USA.

Antiseizure medications (ASM) may contribute to adverse fetal outcomes in pregnant women with epilepsy (WWE). Folate processing (Methylenetetrahydrofolate reductase, MTHFR) gene abnormalities are common in women with epilepsy and depression. L-methylfolate supplements may bypass MTHFR deficiencies, yet their use in WWE during gestation or on fetal development is not well studied. We examine pregnancy histories of three WWE who supplemented with either folate or L-methylfolate and methylcobalamin (methylated B12) during pregnancies. Their pregnancy outcomes improved with L-methylfolate and methylcobalamin supplementation. L-methylfolate and methylcobalamin supplementation merits further study in WWE who have MTHFR mutations, fertility, recurrent miscarriage and or depression histories.
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http://dx.doi.org/10.1016/j.ebr.2020.100419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776832PMC
December 2020

Absolute chemical potentials for complex molecules in fluid phases: A centroid reference for predicting phase equilibria.

J Chem Phys 2020 Dec;153(21):214504

Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, USA.

Solid-fluid phase equilibria are difficult to predict in simulations because bound degrees of freedom in the crystal phase must be converted to free translations and rotations in the fluid phase. Here, we avoid the solid-to-fluid transformation step by starting with chemical potentials for two reference systems, one for the fluid phase and one for the solid phase. For the solid, we start from the Einstein crystal and transform to the fully interacting molecular crystal. For the fluid phase, we introduce a new reference system, the "centroid," and then transform to gas phase molecules. We illustrate the new calculations by predicting the sublimation vapor pressure of succinic acid in the temperature range of 300 K-350 K.
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http://dx.doi.org/10.1063/5.0025844DOI Listing
December 2020

The clinical and cost effectiveness of splints for thumb base osteoarthritis: a randomized controlled clinical trial.

Rheumatology (Oxford) 2020 Nov 30. Epub 2020 Nov 30.

Primary Care Centre of Excellence Versus Arthritis, School of Primary Community and Social Care, Keele University, Staffordshire.

Objectives: To investigate the clinical effectiveness, efficacy and cost effectiveness of splints (orthoses) in people with symptomatic basal thumb joint OA (BTOA).

Methods: A pragmatic, multicentre parallel group randomized controlled trial at 17 National Health Service (NHS) hospital departments recruited adults with symptomatic BTOA and at least moderate hand pain and dysfunction. We randomized participants (1:1:1) using a computer-based minimization system to one of three treatment groups: a therapist supported self-management programme (SSM), a therapist supported self-management programme plus a verum thumb splint (SSM+S), or a therapist supported self-management programme plus a placebo thumb splint (SSM+PS). Participants were blinded to group allocation, received 90 min therapy over 8 weeks and were followed up for 12 weeks from baseline. Australian/Canadian (AUSCAN) hand pain at 8 weeks was the primary outcome, using intention to treat analysis. We calculated costs of treatment.

Results: We randomized 349 participants to SSM (n = 116), SSM+S (n = 116) or SSM+PS (n = 117) and 292 (84%) provided AUSCAN Osteoarthritis Hand Index hand pain scores at the primary end point (8 weeks). All groups improved, with no mean treatment difference between groups: SSM+S vs SSM -0.5 (95% CI: -1.4, 0.4), P = 0.255; SSM+PS vs SSM -0.1 (95% CI: -1.0, 0.8), P = 0.829; and SSM+S vs SSM+PS -0.4 (95% CI: -1.4, 0.5), P = 0.378. The average 12-week costs were: SSM £586; SSM+S £738; and SSM+PS £685.

Conclusion: There was no additional benefit of adding a thumb splint to a high-quality evidence-based, supported self-management programme for thumb OA delivered by therapists.

Trial Registration: ISRCTN 54744256 (http://www.isrctn.com/ISRCTN54744256).
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http://dx.doi.org/10.1093/rheumatology/keaa726DOI Listing
November 2020

Constitutional morphological features and risk of hip osteoarthritis: a case-control study using standard radiographs.

Ann Rheum Dis 2020 Nov 23. Epub 2020 Nov 23.

Academic Rheumatology, University of Nottingham, Nottingham, UK.

Objectives: To evaluate the risk of association with hip osteoarthritis (OA) of 14 morphological features measured on standard antero-posterior pelvis radiographs.

Methods: A case-control study of 566 symptomatic unilateral hip OA cases and 1108 controls without hip OA, using the Genetics of OA and Lifestyle database. Unaffected hips of cases were assumed to reflect pre-OA morphology of the contralateral affected hip. ORs with 95% CI adjusted for confounding factors were calculated using logistic regression. Hierarchical clustering on principal component method was used to identify clusters of morphological features. Proportional risk contribution (PRC) of these morphological features in the context of other risk factors of hip OA was estimated using receiver operating characteristic analysis.

Results: All morphological features showed right-left symmetry in controls. Each feature was associated with hip OA after adjusting for age, gender and body mass index. Increased sourcil angle had the strongest association (OR: 6.93, 95% CI 5.16 to 9.32). Three clusters were identified. The PRC varied between individual features, as well as between clusters. It was 35% (95% CI 31% to 40%) for all 14 morphological features, compared to 21% (95% CI 19% to 24%) for all other well-established risk factors.

Conclusions: Constitutional morphological variation strongly associates with hip OA development and may explain much of its heritability. Relevant morphological measures can be assessed readily on standard radiographs to help predict risk of hip OA. Prospective studies are required to provide further support for causality.
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http://dx.doi.org/10.1136/annrheumdis-2020-218739DOI Listing
November 2020

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials.

Rheumatology (Oxford) 2020 Nov 16. Epub 2020 Nov 16.

Pain Centre Versus Arthritis, Academic Rheumatology, University of Nottingham, Nottingham, UK.

Objectives: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials.

Methods: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant.

Results: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined.

Conclusion: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment.

Clinical Trial Registration: https://clinicaltrials.gov, NCT03146689.
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http://dx.doi.org/10.1093/rheumatology/keaa561DOI Listing
November 2020

Faradization for insomnia: a sleep neurology history.

J Clin Sleep Med 2021 Feb;17(2):249-254

Swedish Epilepsy Center, Seattle, Washington.

None: Insomnia is highly prevalent and challenging to treat. We typically regard insomnia as a disorder of the modern world, but physicians and patients have been struggling with this malady for millennia. Here we present the curious historical practice of using electrization or faradization to treat insomnia. We present methods of application, hypotheses regarding mechanism of action, and historical case reports and case series to better understand this phenomenon. We put faradization for insomnia in the context of the modern use of electrical therapies to support and facilitate human health in multiple different health care arenas. Last, we examine current efforts to use these antiquated concepts to address insomnia through transcranial direct current stimulation and cranial electrical stimulation.
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http://dx.doi.org/10.5664/jcsm.8958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853228PMC
February 2021

The psychology of professional and student actors: Creativity, personality, and motivation.

PLoS One 2020 22;15(10):e0240728. Epub 2020 Oct 22.

Department of Research Methods and Information Science, University of Denver, Denver, Colorado, United States of America.

As a profession, acting is marked by a high-level of economic and social riskiness concomitantly with the possibility for artistic satisfaction and/or public admiration. Current understanding of the psychological attributes that distinguish professional actors is incomplete. Here, we compare samples of professional actors (n = 104), undergraduate student actors (n = 100), and non-acting adults (n = 92) on 26 psychological dimensions and use machine-learning methods to classify participants based on these attributes. Nearly all of the attributes measured here displayed significant univariate mean differences across the three groups, with the strongest effect sizes being on Creative Activities, Openness, and Extraversion. A cross-validated Least Absolute Shrinkage and Selection Operator (LASSO) classification model was capable of identifying actors (either professional or student) from non-actors with a 92% accuracy and was able to sort professional from student actors with a 96% accuracy when age was included in the model, and a 68% accuracy with only psychological attributes included. In these LASSO models, actors in general were distinguished by high levels of Openness, Assertiveness, and Elaboration, but professional actors were specifically marked by high levels of Originality, Volatility, and Literary Activities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580901PMC
December 2020

East Midlands knee pain multiple randomised controlled trial cohort study: cohort establishment and feasibility study protocol.

BMJ Open 2020 09 9;10(9):e037760. Epub 2020 Sep 9.

NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, Nottinghamshire, UK.

Introduction: Knee pain due to osteoarthritis (OA) is a common cause of disability. The UK National Institute for Health and Care Excellence OA guidelines recommend education, exercise and weight loss advice (if overweight) as core interventions before pharmacological adjuncts. However, implementation of these in primary care is often suboptimal. This study aims to develop a complex intervention with non-pharmacological and pharmacological components that can be delivered by nurses. The feasibility and acceptability of the intervention, and feasibility of undertaking a future cohort randomised controlled trial (RCT) will be explored.

Methods And Analysis: In phase 1, we will develop a training programme for nurses and evaluate the fidelity and acceptability of the non-pharmacological element of the intervention. Fidelity checklists completed by the nurse will be compared with video analysis of the treatment sessions. Patients and nurses will be interviewed to determine the acceptability of the intervention and explore challenges to intervention delivery. The non-pharmacological component will be modified based on the findings. In phase 2, we will assess the feasibility of conducting a cohort RCT comprising both the pharmacological and modified non-pharmacological components. We will compare three groups: group A will receive the non-pharmacological components delivered before pharmacological components; group B will receive pharmacological components followed by the non-pharmacological components; and group C (control arm) will continue to receive usual care. Study outcomes will be collected at three time points: baseline, 13 and 26 weeks after randomisation. Qualitative interviews will be conducted with a sample of participants from each of the two active intervention arms.

Ethics And Dissemination: This protocol was approved by the East Midlands-Derby Research Ethics Committee (18/EM/0288) and registered at ClinicalTrials.gov (protocol v4.0, 10/02/2020). The study will be reported in accordance with the Consolidated Standards of Reporting Trials guidance and standards. The results will be submitted for publication in peer-reviewed academic journals.

Trial Registration Number: NCT03670706.
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http://dx.doi.org/10.1136/bmjopen-2020-037760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482502PMC
September 2020

IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.

Front Immunol 2020 23;11:1385. Epub 2020 Jul 23.

Translational Musculoskeletal Research Center & Section of Rheumatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States.

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene () for an association with OA with radiographic severity and symptoms. Cartilage samples from donors ( = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 using explant cultures. Data from two independent Nottinghamshire-based studies ( = 795 and = 613) were used to test genetic variants in the gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 < 0.01) but not with radiographic severity. In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.
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http://dx.doi.org/10.3389/fimmu.2020.01385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390829PMC
April 2021

Individual and herd-level milk ELISA test status for Johne's disease in Ireland after correcting for non-disease-associated variables.

J Dairy Sci 2020 Oct 31;103(10):9345-9354. Epub 2020 Jul 31.

School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, United Kingdom, LE12 5RD.

Antibody-detecting tests for Mycobacterium avium ssp. paratuberculosis (MAP) have low sensitivity and imperfect specificity for detection of infection. Sensitivity increases as the disease progresses. Aside from infection status and stage of disease, several factors affect test performance. These factors have not yet been studied in dairy cows producing lower volumes of milk with higher solids concentration, such as those managed in low-input, pasture-based production systems. Furthermore, the effect of correcting for these associations on individual and herd test status is also unknown. The first objective of this study was to examine the relationship between MAP antibody response in milk and milk yield, somatic cell count (SCC), fat and protein contents, and stage of lactation in dairy cows enrolled in the national Johne's Disease Control Programme (JDCP) in Ireland. The second objective was to examine the effect of correcting the antibody response for these associations on the test status of individual cows and herds, given that individual tests are often used to define a herd's status. Data were extracted for herds in the JDCP from January 2014 to December 2015 inclusive, consisting of 42,657 milk recordings from 18,569 cows across 187 dairy herds. Two linear regression models were constructed to investigate the association between log-transformed MAP sample-to-positive ratio and milk recording data and in primi- and multiparous cows. Days in milk was modeled as a B-spline in each model, and cow and herd were included as random effects. Across both models, natural log-transformed MAP antibody response was negatively associated with milk yield, positively associated with protein and fat production, and had a curvilinear association with log-transformed SCC. The association between MAP antibody response and days in milk varied over the course of the lactation. However, when combined, these variables explained only 5.1% of the variation in the antibody response of the population. After correcting for these associations, 93 multiparous cows and 20 primiparous cows changed category (negative, suspect, or positive). When considered at the herd-test level, out of a total of 531 herd tests, 1 herd changed from negative to positive, and 5 herds changed from positive to negative. This study provides useful information to aid in the interpretation of antibody results for herds testing animals for the presence of MAP infection. At an overall population level, correction of the serological response for non-disease-associated factors has the potential to change the status of only a small number of cows. At the herd level, the proportion of herds changing status was minimal. However, depending on the implications of a herd-level serological diagnosis, consideration should be given to correcting for these non-disease-associated variables within the context of national JD control programs.
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http://dx.doi.org/10.3168/jds.2019-18018DOI Listing
October 2020

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

Neurology 2020 09 20;95(9):e1244-e1256. Epub 2020 Jul 20.

From the Cleveland Clinic Foundation (D.R.N., A.V.A.), OH; California Pacific Medical Center (K.D.L., P.B.W.), San Francisco; Augusta University (A.M.M., Y.D.P.), GA; Henry Ford Hospital (G.L.B.), Detroit, MI; Ohio Health Neuroscience (B.J.S.), Columbus; Swedish Neuroscience Institute (R.P.G., M.J.D.), Seattle, WA; Mayo Clinic Arizona (K.H.N., R.S.Z.), Scottsdale; Johns Hopkins Medicine (G.K.B., W.S.A.), Baltimore, MD; Keck School of Medicine of USC (C.H., C.Y.L.), Los Angeles, CA; Via Christi Epilepsy Center (R.W.L., T.S.), Wichita, KS; Yale University School of Medicine (R.B.D., L.J.H.), New Haven, CT; Mayo Clinic Florida (R.E.W., W.T.), Jacksonville; Columbia University Medical Center (S.S., G.M.M.), New York, NY; University of Texas Southwestern Medical Center (M.A.A.), Dallas; Geisel School of Medicine at Dartmouth (B.C.J., D.W.R.), Hanover, NH; Indiana University School of Medicine (V.S., T.C.W.), Indianapolis; Massachusetts General Hospital (S.S.C., A.J.C.), Boston; Mayo Clinic Minnesota (G.A.W., B.N.L.), Rochester; Medical University of South Carolina (J.C.E., J.J.H.), Charleston; Oregon Health & Science University (D.C. Spencer, L.E.), Portland; Thomas Jefferson University (C.T.S., M.R.S.), Philadelphia, PA; Nicklaus Children's Hospital (I.M.), Miami, FL; Saint Barnabas Medical Center (E.B.G.), Livingston, NJ; University of Rochester Medical Center (M.J.B., A.J.F.), NY; University of Wisconsin Hospital and Clinics (P.R.), Madison; Baylor College of Medicine (A.M.G., E.M.M.), Houston, TX; Emory University School of Medicine (R.E.G.), Atlanta, GA; George Washington University School of Medicine and Health Sciences (D.C. Shields), Washington, DC; Weill Cornell Medical College (T.H.S., D.R.L.), New York, NY; University of Virginia School of Medicine (N.B.F., W.J.E.), Charlottesville; Louisiana State University Health Sciences Center (P.W.O., N.R.V.-P.), New Orleans; University of Florida (S.E., S.N.R.), Gainesville; Wake Forest University Health Sciences (J.G.B.), Winston-Salem, NC; NeuroPace, Inc (T.A.C., F.T.S., C.G.S., K.L.M., T.L.S., M.J.M.), Mountain View; and Stanford University (M.J.M.), Palo Alto, CA.

Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.

Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.

Results: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% ( < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved ( < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators ( < 0.05, 1-tailed χ).

Conclusions: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.

Clinicaltrialsgov Identifier: NCT00572195.

Classification Of Evidence: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
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http://dx.doi.org/10.1212/WNL.0000000000010154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538230PMC
September 2020

Initial analgesic prescriptions for osteoarthritis in the United Kingdom, 2000-2016.

Rheumatology (Oxford) 2021 01;60(1):147-159

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital.

Objectives: To examine trends in the initial prescription of commonly-prescribed analgesics and patient- as well as practice-level factors related to their selection in incident OA.

Methods: Patients consulting with incident clinical OA between 2000-2016 were identified within The Health Improvement Network in the United Kingdom (UK) general practice. Excluded were patients who had history of cancer or were prescribed the analgesics of interest within 6 months before diagnosis of OA. Initial analgesic prescription included oral non-selective NSAID, oral selective cyclooxygenase-2 inhibitor, topical NSAID, paracetamol, topical salicylate or oral/transdermal opioid within 1 month after OA diagnosis.

Results: ∼44% of patients with incident OA (n = 125 696) were prescribed one of these analgesics. Incidence of oral NSAID prescriptions decreased whereas other analgesic prescriptions, including oral opioid prescriptions, increased (all P-for-trend < 0.001). Patients with a history of gastrointestinal disease were more likely to receive topical NSAIDs, paracetamol or oral/transdermal opioids. Only 38% of patients with history of gastrointestinal disease and 21% of patients without it had co-prescription of gastroprotective agent with oral NSAIDs. Oral/transdermal opioid prescription was higher among the elderly (≥65 years), women, obesity, current smoker, and patients with gastrointestinal, cardiovascular or chronic kidney disease. Prescription of oral opioids increased with social deprivation (P-for-trend < 0.05) and was highest in Scotland, whereas transdermal opioid prescription was highest in Northern Ireland (all P-for-homogeneity-test < 0.05).

Conclusion: The initial prescription pattern of analgesics for OA has changed over time in the UK. Co-prescription of gastroprotective agents with oral NSAIDs remains suboptimal, even among those with prior gastrointestinal disease.
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http://dx.doi.org/10.1093/rheumatology/keaa244DOI Listing
January 2021

Corrigendum to: Statin use and risk of joint replacement due to osteoarthritis and rheumatoid arthritis: a propensity-score matched longitudinal cohort study.

Rheumatology (Oxford) 2020 10;59(10):3120

Academic Rheumatology Department, Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1093/rheumatology/keaa223DOI Listing
October 2020

Introduction.

Annu Rev Chem Biomol Eng 2020 06;11:i-ii

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http://dx.doi.org/10.1146/annurev-ch-11-042120-100001DOI Listing
June 2020

Predicting response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: an individual patient data meta-analysis of randomized controlled trials.

Rheumatology (Oxford) 2020 09;59(9):2207-2216

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objectives: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA.

Methods: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction.

Results: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity.

Conclusion: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA.
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http://dx.doi.org/10.1093/rheumatology/keaa113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449808PMC
September 2020

Investigating musculoskeletal health and wellbeing; a cohort study protocol.

BMC Musculoskelet Disord 2020 Mar 21;21(1):182. Epub 2020 Mar 21.

NIHR Biomedical Research Centre, Academic Rheumatology, University of Nottingham Clinical Sciences Building, City Hospital, Nottingham, NG5 1PB, UK.

Background: In an ageing population, pain, frailty and disability frequently coexist across a wide range of musculoskeletal diagnoses, but their associations remain incompletely understood. The Investigating Musculoskeletal Health and Wellbeing (IMH&W) study aims to measure and characterise the development and progression of pain, frailty and disability, and to identify discrete subgroups and their associations. The survey will form a longitudinal context for nested research, permitting targeted recruitment of participants for qualitative, observational and interventional studies; helping to understand recruitment bias in clinical studies; and providing a source cohort for cohort randomised controlled trials.

Methods: IMH&W will comprise a prospective cohort of 10,000 adults recruited through primary and secondary care, and through non-clinical settings. Data collection will be at baseline, and then through annual follow-ups for 4 years. Questionnaires will address demographic characteristics, pain severity (0-10 Numerical Rating Scale), pain distribution (reported on a body Manikin), pain quality (McGill Pain Questionnaire), central aspects of pain (CAP-Knee), frailty and disability (based on Fried criteria and the FRAIL questionnaire), and fracture risk. Baseline characteristics, progression and associations of frailty, pain and disability will be determined. Discrete subgroups and trajectories will be sought by latent class analysis. Recruitment bias will be explored by comparing participants in nested studies with the eligible IMH&W population.

Discussion: IMH&W will elucidate associations and progression of pain, frailty and disability. It will enable identification of people at risk of poor musculoskeletal health and wellbeing outcomes who might be suitable for specific interventions, and facilitate generalisation and comparison of research outcomes between target populations. The study will benefit from a large sample size and will recruit from diverse regions across the UK. Purposive recruitment will enrich the cohort with people with MSK problems with high representation of elderly and unwell people.

Trial Registration: Clinicaltrials.gov NCT03696134. Date of Registration: 04 October 2018.
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http://dx.doi.org/10.1186/s12891-020-03195-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085148PMC
March 2020

Effectiveness of inactivated influenza vaccine in autoimmune rheumatic diseases treated with disease-modifying anti-rheumatic drugs.

Rheumatology (Oxford) 2020 12;59(12):3666-3675

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham.

Objectives: The effectiveness of inactivated influenza vaccine in people with autoimmune rheumatic disease (AIRDs) is not known. We investigated whether the influenza vaccine is effective in preventing respiratory morbidity, mortality and all-cause mortality in AIRD patients.

Methods: Adults with AIRDs treated with DMARDs prior to 1 September of each year between 2006 and 2009, and 2010 and 2015 were identified from the Clinical Practice Research Datalink. Exposure and outcome data were extracted. Data from multiple seasons were pooled. Propensity score (PS) for vaccination was calculated. Cox-proportional hazard ratios (HRs) and 95% CIs were calculated, and were (i) adjusted, (ii) matched for PS for vaccination.

Results: Data for 30 788 AIRD patients (65.7% female, 75.5% with RA, 61.1% prescribed MTX) contributing 125 034 influenza cycles were included. Vaccination reduced risk of influenza-like illness [adjusted HR (aHR) 0.70], hospitalization for pneumonia (aHR 0.61) and chronic obstructive pulmonary disease exacerbations (aHR 0.67), and death due to pneumonia (aHR 0.56) on PS-adjusted analysis in the influenza active periods (IAPs). The associations were of similar magnitude and remained statistically significant on PS-matched analysis except for protection from influenza-like illness, which became non-significant. Sub-analysis restricted to pre-IAP, IAP and post-IAP did not yield evidence of residual confounding on influenza-like illness and death due to pneumonia. Vaccination reduced risk of all-cause mortality, although IAP-restricted analysis demonstrated residual confounding for this outcome.

Conclusion: Influenza vaccine associates with reduced risk of respiratory morbidity and mortality in people with AIRDs. These findings call for active promotion of seasonal influenza vaccination in immunosuppressed people with AIRDs by healthcare professionals.
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http://dx.doi.org/10.1093/rheumatology/keaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733714PMC
December 2020

Performing solvation free energy calculations in LAMMPS using the decoupling approach.

J Comput Aided Mol Des 2020 06 28;34(6):641-646. Epub 2020 Feb 28.

Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana-Champaign, IL, 61801, USA.

The decoupling approach to solvation free energy calculations requires scaling the interactions between the solute and the solution with all intramolecular interactions preserved. This paper reports a new procedure that makes it possible to these calculations in LAMMPS. The procedure is tested against built-in GROMACS capabilities. The model compounds chosen to test our methodology are ethanol and biphenyl. The LAMMPS and GROMACS results obtained are in good agreement with each other. This work should help perform solvation free energy calculations in LAMMPS and/or other molecular dynamics software having no built-in functions to implement the decoupling approach.
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http://dx.doi.org/10.1007/s10822-020-00303-3DOI Listing
June 2020

Statin use and risk of joint replacement due to osteoarthritis and rheumatoid arthritis: a propensity-score matched longitudinal cohort study.

Rheumatology (Oxford) 2020 10;59(10):2898-2907

Academic Rheumatology Department, Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objective: Statins are reported to have a potential benefit on progression of OA and on disease activity in RA, but existing evidence is conflicting. Our objective was to examine whether statins associate with reduction in the risk for joint replacement due to OA and RA.

Methods: This was a propensity score-matched cohort study. Electronic health records from the UK Clinical Practice Research Datalink were used. We selected people prescribed statins and people never prescribed statins. Each statin user was matched to a non-user by age, gender, practice and propensity score for statin prescription. The main outcome measures were knee or hip joint replacement overall, and specifically because of OA or RA. The association between statins and risk of joint replacement was assessed using Cox proportional hazard regression. Statin exposure was categorized according to the potency of reducing low-density lipoprotein as low (21-28%), medium (32-38%) or high (42-55%) intensity.

Results: A total of 178 467 statin users were matched with 178 467 non-users by age, gender, practice and propensity score. Overall, statin was not associated with reduced risk of knee or hip replacement (hazard ratio 0.99, 95% CI: 0.97, 1.03), unless prescribed at high strength (0.86, 0.75-0.98). The reduced risk was only observed for joint replacement due to RA (0.77, 0.63-0.94) but not OA (0.97, 0.94-1.01).

Conclusion: Statins at high intensity may reduce the risk of hip or knee replacement. This effect may be RA specific. Further studies to investigate mechanisms of risk reduction and the impact in people with RA are warranted.
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http://dx.doi.org/10.1093/rheumatology/keaa044DOI Listing
October 2020

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

Epilepsia 2020 03 18;61(3):408-420. Epub 2020 Feb 18.

NeuroPace, Inc., Mountain View, CA, USA.

Objective: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system.

Methods: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection.

Results: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets.

Significance: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.
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http://dx.doi.org/10.1111/epi.16442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154711PMC
March 2020

Brain perfusion patterns are altered in chronic knee pain: a spatial covariance analysis of arterial spin labelling MRI.

Pain 2020 06;161(6):1255-1263

Versus Arthritis Pain Centre, University of Nottingham, Nottingham, United Kingdom.

Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.
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http://dx.doi.org/10.1097/j.pain.0000000000001829DOI Listing
June 2020

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

Rheumatology (Oxford) 2020 09;59(9):2544-2549

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, AucklandNew Zealand.

Objective: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout.

Methods: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed.

Results: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83).

Conclusion: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.
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http://dx.doi.org/10.1093/rheumatology/kez685DOI Listing
September 2020